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PubMed2025

Immune-mediated indirect interaction between gut microbiota and bacterial pathogens.

BACKGROUND: In many animals, survival during infection depends on the ability to coordinate interactions between the host immune system and gut microbiota. These tripartite interactions, in turn, potentially shape pathogen virulence evolution. A key regulator of the immune system and, hence, bipartite interactions in insects is the immune deficiency (Imd) pathway, which modulates gut microbiota and pathogens by synthesizing antimicrobial peptides (AMPs) through the NF-κB transcription factor Relish. However, whether Imd-dependent AMPs mediate indirect interactions between gut microbiota and pathogens in a tripartite context remains unclear. Using RNAi-mediated knockdown of Tenebrio molitor Relish (TmRelish), we hypothesized that Imd-dependent AMPs influence indirect interaction between Providencia burhodogranariea_B (P. b_B) infection and the gut microbiota. RESULTS: TmRelish knockdown altered bipartite interactions by disrupting gut microbiota load and composition, increasing pathogen load, and ultimately leading to higher host mortality during infection. However, we did not find support for our tripartite hypothesis that Imd-dependent AMPs mediate indirect interactions between the gut microbiota and P. b_B infection, suggesting the involvement of alternative regulatory pathways or Imd-independent mechanisms. Nevertheless, our investigations of tripartite interactions showed a positive effect of P. b_B infection on gut microbiota load, which in turn stimulated the expression of a subset of AMPs. However, this upregulation of AMPs did not result in reduced P. b_B load. Notably, the gut microbiota did not affect pathogen load but promoted host survival during P. b_B infection, indicating a role in increasing host tolerance rather than resistance. CONCLUSIONS: These findings suggest that while Imd-dependent AMPs may not mediate tripartite interactions in our system, microbiota-host interactions, such as microbiota-mediated immune priming and changes in microbiota load, can shape infection outcomes. These effects on infection outcomes almost certainly exert important selective pressures on the evolution of bacterial virulence.

Animals↗
PubMed2026

Rasputin/G3BP mediates subversion of antiviral immunity by o'nyong-nyong virus in Anopheles coluzzii.

Cellular G3BP proteins are essential for alphavirus infection in both vertebrate and mosquito hosts, but the underlying mechanism of their proviral activity is poorly understood in any host. Whether the mosquito G3BP ortholog, Rasputin (Rin), interacts with host immunity to influence alphavirus infection has not been investigated, and anopheline mosquito interactions with arboviruses have been little studied. Here, we find that Rin silencing in Anopheles mosquitoes results in decreased ONNV infection levels, indicating a proviral activity for Anopheles Rin. We find that Rin function is required to maintain basal activity of the antiviral Imd and JAK/STAT pathways in uninfected mosquitoes. However, during ONNV infection, the control of the Imd pathway by Rin activity appears corrupted because Rin silencing leads to overexpression of the Imd positive regulator, Rel2. Thus, silencing of Rin both augments Rel2 transcript abundance and decreases ONNV load. Co-silencing of Rel2 with Rin restores normal ONNV infection levels, indicating that Rin activity is required to inhibit Imd function during ONNV infection, and which explains most of the Rin proviral phenotype. In addition, we show that the ONNV non-structural protein 3 (nsP3), which binds to Rin, strongly alters the pattern of Anopheles cellular protein partners interacting with Rin. In the presence of ONNV nsP3, 48 Rin-binding host proteins are unchanged but seven binding proteins are excluded and eight new cellular proteins bind Rin. The altered cellular protein partners are candidate host factors involved in viral subversion of Rin control over Imd activity. Overall, these results reveal a molecular mechanism in which ONNV, probably through nsP3, co-opts the normal Rin function for basal cellular immune activity by subverting the Imd antiviral pathway to promote infection. These results may be generalizable for Rin function during alphavirus infection of other mosquitoes, as well as for G3BP function in the mammalian host, and could offer a target for development of vector-based genetic control tools against arbovirus transmission.

Animals↗
PubMed2026

[Mechanism of Tianshu Capsules in treating migraine rats based on gut microbiota].

This study aims to investigate the therapeutic effect of Tianshu Capsules(TS) on migraine rat model and explore its potential mechanism of action from the perspectives of the structure of the gut microbiota and functional pathway regulation. A migraine rat model was established via subcutaneous injection of nitroglycerin. The Sprague-Dawley rats were randomly divided into a control group, a model group, a low-dose TS group, a medium-dose TS group, a high-dose TS group, and an ibuprofen group. The efficacy of TS in improving migraine was evaluated by general condition observation and measurement of the craniofacial pain threshold. The expression of the gene c-fos in the trigeminal ganglion was determined by quantitative real-time polymerase chain reaction(PCR). The contents of endothelin-1(ET-1), calcitonin gene-related peptide(CGRP), and 5-hydroxytryptamine(5-HT) in serum were measured by enzyme-linked immunosorbent assay(ELISA). Fecal samples were subjected to metagenomic sequencing for systematic analysis of gut microbial diversity, taxonomic composition difference, and functional pathway changes of Kyoto Encyclopedia of Genes and Genomes(KEGG), and their correlations with behavioral and biochemical indices were further evaluated. The results show that TS significantly improves the increased body temperature and decreased craniofacial pain threshold in migraine rats. It also markedly suppresses the elevated expression levels of the gene c-fos in the trigeminal ganglion and reduces the levels of ET-1, CGRP, and 5-HT in serum. Metagenomic beta diversity analysis and differential taxonomic abundance analysis reveal that the migraine model induces significant gut microbiota dysbiosis, characterized by enrichment of harmful genera, including Streptococcus and Enterococcus, as well as a decline in the abundance of beneficial bacteria such as Allobaculum, Eubacterium, and Muribaculum. Functional pathway analysis results of KEGG further reveal that the relative abundances of pathways associated with biosynthesis of phenylalanine, tyrosine, and tryptophan, bacterial secretion system, citrate cycle, and biosynthesis of secondary metabolites are significantly decreased in the model group. TS intervention increased the abundance of the genus, such as Parabacteroides, Eubacterium, Allobaculum, and Muribaculum, while decreasing levels of microbiota, including Staphylococcus. TS also significantly upregulated pathways associated with barrier function(tight junction), amino acid biosynthesis pathways, and biosynthesis pathways of neurotransmitter precursors such as cysteine and methionine metabolism. In addition, it downregulated inflammatory pathways(Toll and IMD signaling) and pathways related to Staphylococcus aureus infection, thereby restoring the structure and function of the microbiota to a state close to those of the normal group. Spearman correlation analysis reveals that partial gut microbiota are significantly associated with migraine-related behavioral and biochemical indices(c-fos, ET-1, CGRP, and 5-HT). In conclusion, TS can regulate the disrupted gut microbiota structure and microbial functions related to neurotransmitter metabolism, intestinal barrier function, and inflammatory regulation in migraine model rats, which may be one of the potential key ways through which TS exert its anti-migraine effect.

Animals↗
PubMed2026

Insect immune systems: same same but different but still same.

Insects are the most diverse group of animals in nature, occupying nearly every ecological niche and playing central roles as pollinators, pests, and disease vectors. Despite this vast diversity, insects rely on a set of conserved yet evolutionarily adaptable immune pathways to defend against pathogens. Early studies in insect immunity have laid the foundation for human immunology, and recent advances in genomic and transgenic technologies have renewed interest in understanding how immune responses vary across insect orders. Insects are highly diverse in their immune systems; each species has unique immune responses that help fight infections from specific pathogens. Nevertheless, they share multiple aspects of recognition, regulation, and effector mechanisms. This review focuses on current knowledge of the immune systems of major insect lineages to highlight both shared signaling pathways, immune cells, and humoral factors, as well as lineage-specific responses that reflect distinct ecological pressures that have shaped the host-microbe interactions. Comparing different insect species and orders not only provides insights into the evolutionary divergences and convergences of immune system features but also offers complementary knowledge among species within the same order, helping fill existing gaps. Understanding these evolutionary patterns not only deepens our understanding of insect immunity but also informs the development of transgenic strategies to disrupt pathogen transmission in key vector species.

Animals↗
PubMed2025

A genome-wide survey reveals a diverse array of enhancers coordinate the Drosophila innate immune response.

To defend against microbes, animals regulate a complex immune response. The Drosophila innate immune system deploys a large transcriptional induction of signaling proteins, antimicrobial effectors, and other critical immune factors. This transcriptional response is encoded in enhancers, cis-regulatory sequences that modulate gene expression by binding transcription factors (TFs). While enhancers and transcription factor binding sites (TFBS) have been identified for several immune responsive genes in Drosophila, most enhancers that regulate immune-induced genes are unknown. By identifying enhancers, we can understand how their composition controls expression and contributes to infection outcome. We employed STARR-seq (Self Transcribing Active Regulatory-Region sequencing) in a hemocyte-like cell line to identify immune-specific enhancers across the D. melanogaster genome and performed ATAC-seq in hemocytes extracted from adult flies to assess the chromatin state of these enhancers before and after immune stimulus. We identified thousands of enhancers responsive to IMD stimulation, one of the two primary immune signaling pathways in Drosophila. As expected, immune enhancers are enriched for motifs of Relish, an NF-κB factor, and Kay/Jra, a bZip heterodimer pair, involved in the Imd and JNK pathways respectively, compared to enhancers active in unstimulated cells. However, when grouping enhancers by their target gene's expression timing or functional role or by the enhancers' chromatin accessibility pre- or post-stimulus, different groups of TFBS motifs are enriched, suggesting distinct regulatory logic for different parts of the immune response. Identification and characterization of the diverse array of enhancers that regulate the innate immune response expands our understanding of how animals fight infections.

Drosophila immunity↗
PubMed2026

Respiratory manifestations as clues to inherited metabolic disorders in children: a phenotype-driven diagnostic approach.

UNLABELLED: Inherited metabolic disorders (IMDs) are uncommon but clinically important causes of respiratory morbidity in children. Respiratory involvement may be the first or dominant manifestation, although it may precede, accompany, or follow systemic involvement. Because cough, dyspnea, hypoxemia, recurrent infection, abnormal chest imaging, and ventilatory failure are non-specific, affected children may initially be managed for common respiratory conditions, such as infection, asthma, aspiration, immunodeficiency, or non-metabolic diffuse lung disease, before the underlying IMD is recognized. This narrative mini-review presents a phenotype-driven approach to recognizing IMDs in pediatric respiratory practice. Rather than cataloguing rare disorders by metabolic pathway, it organizes respiratory involvement into practical clinical entry points: diffuse lung disease, pulmonary alveolar proteinosis-like disease, pulmonary vascular disease, recurrent infection or bronchiectasis, upper-airway or thoracic restriction, and neuromuscular respiratory failure and aspiration. For each pattern, we highlight extrapulmonary red flags and first-line biochemical, enzymatic, and genetic tests that may guide early etiological diagnosis. CONCLUSION: Careful recognition of respiratory phenotypes, combined with targeted metabolic and genomic evaluation, may shorten diagnostic delay and allow disease-specific treatment before irreversible pulmonary or neurological injury occurs. WHAT IS KNOWN: • IMDs can involve the respiratory system and may mimic common pediatric respiratory disorders or non-metabolic forms of childhood diffuse lung disease. • Respiratory manifestations may precede, accompany, or follow classical systemic features, and their temporal pattern varies among individual IMDs. WHAT IS NEW: • This mini-review organizes IMD-related respiratory involvement by presenting respiratory phenotype rather than by metabolic pathway. • It links respiratory entry points with extrapulmonary red flags and targeted biochemical, enzymatic, and genetic testing to support earlier diagnosis.

Humans↗
PubMed2026

Comparative in silico analysis of Apis mellifera immune responses to Varroa destructor and Tropilaelaps mercedesae: Common and mite-specific molecular signatures.

Parasitic mites Varroa destructor and Tropilaelaps mercedesae represent major threats to global honey bee (Apis mellifera) health and productivity, yet comparative molecular insights into host responses remain limited. To address this, we systematically compiled published studies (2015-2025) reporting genes associated with honey bee interactions with V. destructor (11 studies, 87 genes), T. mercedesae (4 studies, 35 genes), and hygienic behavior (6 studies, 44 genes). Gene identifiers were harmonized to the Amel_HAv3.1 genome assembly, yielding three non-redundant sets: 64 Varroa-associated, 34 Tropilaelaps-associated, and 44 hygienic behavior-associated genes. Venn analysis identified 10 overlapping genes (including A0A088A8D5, A0A088ADL8, ABAE_APIME, Def1, Def2, Gapdh, HYTA_APIME, Imd, LOC726783, and Vg), suggesting conserved defense mechanisms, while 41 and 24 genes were uniquely associated with Varroa and Tropilaelaps, respectively. Enrichment analyses revealed Varroa-responsive genes were enriched in immune processes, chitin catabolism, and signaling pathways (Toll/Imd, MAPK, Wnt). Tropilaelaps-associated genes were enriched for antibacterial defense and stress response, with Toll/Imd signaling as the sole significantly enriched pathway. Overlapping genes reinforced core innate immunity activation. Protein-protein interaction network centrality analysis identified key hub genes: Def1, HYTA_APIME, ABAE_APIME, PPO, Imd, PGRP-LC, Vg for Varroa; and ACPH1_APIME, MRJP1, Vg, LOC726783 for Tropilaelaps. Results demonstrate that, despite differences in mite biology, honey bees show a conserved immune response against both parasites, centered on antibacterial defense, humoral immunity, and activation of the Toll/Imd pathway. Although limited by the in-silico nature and research asymmetries reflecting Tropilaelaps' emergence, this curated resource establishes a comprehensive framework for elucidating shared and distinct molecular defense mechanisms. Ultimately, this approach prioritizes diagnostic markers and candidate genes for functional validation and breeding strategies to enhance colony resilience against mite‑driven disease globally.

Animals↗